title: Comparison of corticotropin-releasing factor, dexamethasone, and temozolomide: treatment efficacy and toxicity in U87 and C6 intracranial gliomas.
abstract: PURPOSE/EXPERIMENTAL DESIGN: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide.
  
  
  RESULTS
  In vitro combination therapy and monotherapy showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control--41 days (95% CI 25-61); "low-hCRF" 74.5 days (95% CI 41-88); "high-hCRF" >130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were similar treatment toxicities. The difference in hCRF treatment response between U87 and C6 intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87 xenografts; no CRF receptors were identified in C6 xenografts.
  
  
  CONCLUSIONS
  hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas.
authors.affiliation: Department of Neurology and Radiology, Sloan Kettering Institute Molecular Pharmacology and Chemistry Program, Inc, New York, NY 10065, USA.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Moroz
authors.forename: Ruimin
authors.initials: R
authors.lastname: Huang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kochetkov
authors.forename: Weiji
authors.initials: W
authors.lastname: Shi
authors.forename: Howard
authors.initials: H
authors.lastname: Thaler
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Idoia
authors.initials: I
authors.lastname: Gamez
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ryan
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003346:Corticotropin-Releasing Hormone / Q000627:therapeutic use*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D000077204:Temozolomide; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D000077204:Temozolomide